Seronegative Lyme Disease: Can Borrelia Be Cultured?

Seronegative Lyme disease may be missed
Negative tests do not always exclude Lyme disease
Clinical history and symptoms still matter

Seronegative Lyme disease remains one of the more challenging clinical scenarios in tick-borne illness. Patients may present with symptoms consistent with Lyme disease despite negative laboratory testing, creating uncertainty for both clinicians and patients.

Scientists are increasingly focusing attention on tick-borne pathogens present in the Southeastern United States. In 2015, Lantos and colleagues reviewed the geographic expansion of Lyme disease in the Southeast and found “a marked increase in Lyme disease cases in Virginia, particularly from 2007 onwards … with development of a new disease cluster in the southern Virginia mountain region.”

Since 2009, five counties in North Carolina have been considered endemic for Lyme disease. The introduction of tick-transmitted diseases into new areas is likely to continue, raising concern that patients outside traditionally recognized endemic regions may still be overlooked.

Rudenko and colleagues’ study of 24 individuals examined patients from the Southeast who had already been treated for suspected tick-borne illness. Three individuals were from North Carolina, 11 from Georgia, and 10 from Florida. Among participants, 71% recalled a tick bite and 50% reported lesions resembling tick bites.

The authors described these patients as individuals with “undefined disorders” who had symptoms atypical for Lyme borreliosis but had undergone antibiotic treatment because Lyme disease remained clinically suspected despite being seronegative.

Major symptoms included severe headache, nausea, muscle and joint pain, numbness and tingling, neck pain, back pain, panic attacks, depression, dizziness, vision problems, sleep problems, and shortness of breath.

The researchers successfully cultivated Borrelia burgdorferi and Borrelia bissettii-like organisms from these patients. Their findings raised questions about whether some patients with persistent symptoms and negative testing may still harbor evidence of Borrelia infection.

Why can Lyme disease tests be negative?

Several factors may contribute to false-negative or seronegative presentations:

• Testing performed too early in infection
• Variation in immune response between individuals
• Prior antibiotic exposure
• Differences among Borrelia species or strains
• Laboratory limitations

These limitations are one reason clinicians often rely on a combination of exposure history, symptoms, physical findings, and laboratory data when evaluating suspected Lyme disease.

Patients with unexplained neurologic symptoms, fatigue, pain syndromes, or autonomic symptoms may overlap with presentations discussed in Lyme disease symptoms and delayed Lyme disease diagnosis.

Why Borrelia burgdorferi Is Difficult to Culture

One reason seronegative Lyme disease remains controversial is that Borrelia burgdorferi is difficult to culture. Unlike many bacterial infections, Borrelia grows slowly and requires specialized laboratory techniques.

A modified Kelly-Pettenkofer medium was used instead of standard BSK-H culture media. Positive cultures underwent DNA purification, PCR amplification, sequencing, and electron microscopy.

These technical challenges help explain why culturing Borrelia is rarely performed in routine clinical practice and why negative testing may not always answer every clinical question.

Frequently Asked Questions

Can Lyme disease be present despite negative tests?

Yes. Some patients may have symptoms consistent with Lyme disease despite negative serology, particularly early in illness or after antibiotic exposure.

What is seronegative Lyme disease?

Seronegative Lyme disease refers to cases where Lyme disease is suspected clinically but antibody-based testing remains negative.

Why is Borrelia burgdorferi difficult to culture?

Borrelia species are slow-growing organisms that require specialized media and laboratory techniques, making routine culture impractical.

Does a negative test rule out Lyme disease?

No. Laboratory results are one component of assessment and should be interpreted alongside symptoms, exposure history, and examination findings.

Clinical Takeaway

Seronegative Lyme disease remains controversial and difficult to study. However, this report highlights that patients with compatible symptoms and exposure histories may not fit neatly into laboratory definitions.

Negative testing should be interpreted cautiously when the clinical picture continues to suggest Lyme disease.

Related Articles

These articles explore related diagnostic challenges and symptom patterns:

Delayed Lyme disease diagnosis
Persistent Lyme disease symptoms
Why Lyme tests medicine
Neurologic Lyme disease

References

1. Lantos PM, Nigrovic LE, Auwaerter PG, et al. Geographic Expansion of Lyme Disease in the Southeastern United States, 2000–2014. Open Forum Infect Dis. 2015;2(4):ofv143.
2. Rudenko N, Golovchenko M, Vancova M, Clark K, Grubhoffer L, Oliver JH. Isolation of live Borrelia burgdorferi sensu lato spirochetes from patients with undefined disorders and symptoms not typical for Lyme borreliosis. Clin Microbiol Infect. 2015.
3. Rudenko N, Golovchenko M, Mokracek A, et al. Detection of Borrelia bissettii in cardiac valve tissue of a patient with endocarditis and aortic valve stenosis. J Clin Microbiol. 2008;46(10):3540-3543.
4. Rudenko N, Golovchenko M, Ruzek D, et al. Molecular detection of Borrelia bissettii DNA in serum samples from patients with suspected borreliosis. FEMS Microbiol Lett. 2009;292(2):274-281.
5. Girard YA, Fedorova N, Lane RS. Genetic diversity of Borrelia burgdorferi and detection of B. bissettii-like DNA in serum samples. J Clin Microbiol. 2011;49(3):945-954.

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Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.

Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention